The present invention relates to a novel process whereby the racemic derivatives of a substituted 5-(pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid are separated via a unique resolution method into pure 1- and d-isomers. Derivatives of substituted 5-(pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid are disclosed in U.S. Pat. No. 4,511,724 issued to Michael N. Chang and Tesfaye Biftu. These compounds are useful as anti-inflammatory and analgesic agents.
Previously, the separation of a racemic mixture of diastereomers could be accomplished by high pressure liquid chromatography (HPLC) and fractional crystallization. However, the overall yield of these well-established methods, as applied to compounds referred to in the present invention, are very poor. In particular, the HPLC method is impractical when large quantities of a pure diastereomer are required.
It has been known that by relying on the difference in solubilities of two diastereomers in a chosen solvent system, efficient separation can be achieved. Applying this principle to the compounds referred to in the present invention, for example, ethyl 5-(1-methyl-5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2- a]pyrrole-1-carboxylate, a 83% improvement of yield over the conventional methods was observed.